The instant invention relates to solid molecular dispersions of one or more psychoactive substantially insoluble 2-aryl-pyrazolo [4,3-C]quinolin-3-ones in polyvinylpyrolidone (PVP) exhibiting enhanced absorption upon oral administration, and a method of treating anxiety or depression in mammals by orally administering to the mammal in need thereof an effective amount of such molecular dispersion.
The psychoactive 2-aryl-pyrazolo[4,3-C]quinolin-3-ones for use in preparing the molecular dispersions having enhanced absorption characteristics are described in U.S. Pat. No. 4,312,870, issued Jan. 26, 1982. In general, however, the psychoactive compounds and their pharamaceutically acceptable salts exhibit poor solubility characteristics in water, gastric fluid and intestinal fluid. Also such compounds tend to exhibit erratic absorption characteristics upon oral administration to mammals in conventional forms.
A number of studies are reported regarding the dissolution rates of various poorly soluble drugs in various polymer dispersions. For example, Simonelli et al., J. Pharm. Sci., 58(5), 538-549 (1969), discussed the increased rate of solution of sulfathiazole from tablets wherein the sulfathiaziole is previously coprecipitated with PV. As cautioned by the author, at Page 539 thereof, in order for the drug to be released from the polymer, the rate of solvent interation must be greater than the rate of intact complex dissolution, otherwise the drug will remain bound as a drug-polymer complex; and moreover, the rate of drug dissolution may be restricted by the amount of free drug in solution, for if the free drug concentration exceeds its solubility, precipitation of the unbound drug may occur on the surface of the dissolving complex, thereby adversely affecting further drug dissolution. Moreover, the stability of such two component systems is unpredictable since solid-solid phases may be unstable on storage, dur to the existence of a metastable system. This problem was recognized by Allen et al., J. Pharm. Sci., 58(10), 1190-1193 (1969). Accordingly, more complicated multi-component compositions have been proposed to increase the bioavailability of poorly soluble drugs. For example, U.S. Pat. No. 3,862,311, issued Jan. 21, 1975 discloses the combination of a drug, such as progesterone, a water soluble polymer and a nonionic surfactant, such as an ethylene oxide/propylene oxide polycondesate, to enhance in-vivo absorption of the drug.
It has now been found that psychoactive 2-arly-pyrazolo[4,3-C]quinolin-3-ones which are themselves substantially insoluble in water, gastric fluid and intestinal fluid can be formulated to substantially increase the bioavailability thereof upon oral administration by providing a solid molecular dispersion thereof in polyvinylpyrrolidone.
It is an object of the instant invention to provide such compositions.
It is a further object of the instant invention to provide a method of treating a mammal by the oral administration of such compositions.
It is yet a further object of the instant invention to provide methods for preparing such compositions.
These and other objects of the invention are apparent from the following detailed description of the invention.